Cineole inhibits the biosynthesis of leukotrienes and prostaglandins to alleviate allergic rhinitis: Insights from metabolomics.

Allergic rhinitis (AR) is a common allergic disease characterized by nasal congestion, rhinorrhoea, and sneezing. Cineole, a monoterpenoid compound widely present in various volatile oils, has a wide range of pharmacological activities and is of interest in allergic airway diseases for its anti-inflammatory and anti-mucus production abilities. However, the protective effects of cineole in mice with allergic rhinitis and its mechanisms have not been well investigated. In this study, the protective effect of cineole against ovalbumin-induced (OVA-induced) allergic rhinitis and its molecular mechanism is investigated by metabolomic analysis based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). OVA combined with aluminum hydroxide adjuvant is used to sensitize and establish the allergic rhinitis (AR) mouse model. The mice are randomly divided into groups of control, AR, cineole (30 mg/kg), and budesonide (38.83 µg/kg). The pharmacodynamic results show that cineole significantly reduces the levels of Th2-type cytokines and OVA-specific IgE (OVA-sIgE) in AR mice, improves nasal mucosal tissue damage and alleviates nasal symptoms compared to the untreated AR group. Metabolomic results show that arachidonic acid (AA) metabolism and tryptophan (Trp) metabolism are reprogrammed on the basis of 27 significantly altered metabolites. Further studies show that cineole inhibits the biosynthesis of pro-inflammatory lipid mediators leukotrienes (LTs) and prostaglandins (PGs) in mice by inhibiting the activity of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) in the arachidonic acid metabolic (AA metabolic) pathway. It also inhibits the production of Th2 cytokines and inflammatory cell infiltration, thereby alleviating symptoms such as nasal congestion and nasal leakage. These results reveal the action and molecular mechanism of cineole in alleviating AR and provide a theoretical basis for the clinical application of cineole in treating AR.

Phytochemical Estimation and Therapeutic Amelioration of Aesculus hippocastanum L. Seeds Ethanolic Extract in Gastric Ulcer in Rats Possibly by Inhibiting Prostaglandin Synthesis.

OBJECTIVE: To quantify phytochemicals using liquid chromatography and mass spectroscopy (LCMS) analysis and explore the therapeutic effect of Aesculus hippocastanum L. (AH) seeds ethanolic extract against gastric ulcers in rats. METHODS: Preliminary phytochemical testing and LCMS analysis were performed according to standard methods. For treatment, the animals were divided into 7 groups including normal control, ulcer control, self-healing, AH seeds low and high doses, ranitidine and per se groups. Rats were orally administered with 10 mg/kg of indomethacin, excluding the normal control group (which received 1% carboxy methyl cellulose) and the per se group (received 200 mg/kg AH seeds extract). The test group rats were then given 2 doses of AH seeds extract (100 and 200 mg/kg, respectively), while the standard group was given ranitidine (50 mg/kg). On the 11th day, rats in all groups were sacrificed, and their stomach was isolated to calculate the ulcer index, and other parameters such as blood prostaglandin (PGE2), tissue superoxide dismutase (SOD), catalase (CAT), malonyldialdehyde (MDA), and glutathione (GSH). All isolated stomach tissues were analyzed for histopathological findings. RESULTS: The phytochemical examination shows that the AH seeds contain alkaloids, flavonoids, saponins, phenolic components, and glycosides. LCMS analysis confirms the presence of quercetin and rutin. The AH seeds extract showed significant improvement in gastric mucosa conditions after indomethacin-induced gastric lesions (P<0.01). Further marked improvement in blood PGE2 and antioxidant enzymes, SOD, CAT, MDA and GSH, were observed compared with self-healing and untreated ulcer-induced groups (P<0.01). Histopathology results confirmed that AH seeds extract improved the mucosal layer and gastric epithelial membrane in treated groups compared to untreated ulcer-induced groups. CONCLUSIONS: LCMS report confirms the presence of quercetin and rutin in AH seeds ethanolic extract. The therapeutic effect of AH seeds extract against indomethacin-induced ulcer in rat model indicated the regenerated membrane integrity, with improved cellular functions and mucus thickness. Further, improved antioxidant enzyme level would help to reduce PGE2 biosynthesis.

Pulmonary pressure recovery in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension: determinants and clinical impact.

BACKGROUND: Over the past two decades randomized controlled trials of combination treatments for Pulmonary Arterial Hypertension (PAH) have demonstrated improvements of clinical status but only modest reductions in mean pulmonary arterial pressure (mPAP). Recent experiences with upfront combination treatments including parenteral prostacyclins have shown more substantial mPAP reductions, and have provided grounds for reconsiderations of treatment. OBJECTIVES: To evaluate the possibility of achieving mPAP <25 mmHg with current treatments, its determinants and the prognostic impact of mPAP reduction. METHODS: 267 consecutive idiopathic, hereditary and drug and toxin-induced PAH patients treated with targeted therapies from three expert centers were followed with periodic clinical and hemodynamic assessments for survival detection. RESULTS: Fifty-four (20.2%) patients achieved a mPAP <25 mmHg over 58 months (IQR 27-90) of treatment. Determinants of mPAP <25 mmHg were mPAP at diagnosis (HR 0.96, 95C.I. 0.93-0.98, p = 0.002) and an upfront combination strategy (double oral combination: HR 2.3, 95C.I. 1.10-4.76, p = 0.02; one oral plus parenteral prostanoid: HR 3.6, 95C.I. 1.39-9.37, p = 0.008; triple combination employing parenteral prostanoids: HR 12.9, 95C.I. 4.9-33.2, p = 0.0001). Seventy-three patients (27.3%) died. Survival rates were 90%, 79%, 70%, 55%, and 42% at 1, 3, 5, 10, and 15 years, respectively. Mean PAP during follow-up, days from diagnosis to prostanoid initiation and prostanoid maximum dose emerged as independent predictors of survival (Uno-C-index: 0.85). A mPAP ≤35 mmHg during follow-up was identified as the best cutoff value for prediction of survival. CONCLUSIONS: Reduction to a mean PAP ≤ 35 mmHg appears to be a meaningful treatment target in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension.

Oral exposure to DEHP may stimulate prostatic hyperplasia associated with upregulation of COX-2 and L-PGDS expressions in male adult rats.

Di-(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine disruptor (EED), can disrupt estrogen and androgen secretion and metabolism process, thus inducing dysfunctional reproduction such as impaired gonadal development and spermatogenesis disorder. Prostaglandin synthases (PGS) catalyze various prostaglandins biosynthesis, involved in inflammatory cascade and tumorigenesis. Yet, little is known about how PGS may impact prostatic hyperplasia development and progression. This study concentrates predominantly on the potential prostatic toxicity of DEHP exposure and the mediating role of PGS. In vivo study, adult male rats were administered via oral gavage 30 µg/kg/d, 90 µg/kg/d, 270 µg/kg/d, 810 µg/kg/d DEHP or vehicle for four weeks. The results elucidated that low-dose DEHP may cause the proliferation of the prostate with an increased PCNA/TUNEL ratio. Given the importance of estrogens and androgens in prostatic hyperplasia, our first objective was to evaluate the levels of sex hormones. DEHP improved the ratio of estradiol (E2)/testosterone (T) in a dose-dependent manner and upregulated estrogen receptor alpha (ERα) and androgen receptor (AR) expressions. Prostaglandin synthases, including cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), were significantly upregulated in the ventral prostate. COX-2 and L-PGDS might mediate the tendency of prostatic hyperplasia induced by low-dose DEHP through estradiol/androgen regulation and imbalance between proliferation and apoptosis in vivo. These findings provide the first evidence that prostaglandin synthases contribute to the tendency toward benign prostatic hyperplasia induced by DEHP. Further investigations will have to be performed to facilitate an improved understanding of the role of prostaglandin synthases in DEHP-induced prostatic lesions.

Altered expression of Notch signaling, Tlr receptors, and surfactant protein expression after prostaglandin inhibition may be associated with the delayed labor in LPS-induced mice.

PURPOSE: This study aims to investigate whether indomethacin (IND) delays preterm birth by regulating the Notch pathway, Tlr receptors, and Sp-A in the placenta in lipopolysaccharide (LPS)-induced preterm labor (PTL) model. METHODS: CD-1 mice were distributed to the pregnant control (PC), Sham, PBS, IND (2 mg/kg; i.p.), LPS (25 µg/100 µl; intrauterine), and LPS + IND groups. The injections were performed on day 14.5 of pregnancy. Placentae were collected on day 15.5 of pregnancy, and immunohistochemical analyzes were performed. Differences in staining intensities between the Cox-1, Notch-1 (N1), Dll-1, Jagged-2 (Jag-2), Tlr-2, and Tlr-4 proteins were compared. RESULTS: Preterm labor rates were 100% and 66% (preterm delivery delayed 5 h) in the LPS and LPS + IND groups, respectively. In LPS-treated mice, a general morphological deterioration was observed in the placenta. Total placental mid-sagittal measurement was significantly reduced in the LPS-treated group, while it was similar to the PC group in the LPS + IND group. Cox-1 expression in the LZ increased, and Sp-A expression decreased after LPS injection, and IND administration diminished this increase. N1 expression increased in the labyrinth zone (LZ) and the junctional zone (JZ). Dll-1 and Jag-2 expression increased in the JZ after LPS injection (p < 0.0001). IND administration diminished Tlr-2 expression in the LZ and Tlr-4 expression in the JZ after LPS injection. CONCLUSION: In conclusion, PG (prostaglandin) inhibition may alter Notch signaling, Tlr, and Sp-A protein expression and may be associated with delayed labor in LPS-induced mice.

Prostaglandins for induction in pregnancies with fetal growth restriction.

BACKGROUND: The data on safety of prostaglandin agents for induction of pregnancies with fetal growth restriction is limited. OBJECTIVE: To compare the rates of adverse outcomes among pregnancies with fetal growth restriction undergoing induction of labor with and without prostaglandins STUDY DESIGN: We performed a propensity-score-based secondary analysis of the Consortium on Safe Labor database. We included term, singleton, and nonanomalous pregnancies with fetal growth restriction (estimated fetal weight <10th percentile for gestational age). We excluded previous cesarean deliveries. The primary exposure was induction using prostaglandins (prostaglandin E1 or prostaglandin E2) compared with other methods. The primary outcome was a composite of adverse neonatal outcomes. The secondary outcomes included all cesarean deliveries and cesarean deliveries for nonreassuring fetal heart tracings. A subgroup analysis comparing the type of prostaglandin was planned a priori. The results are expressed as adjusted odds ratios with 95% confidence intervals. RESULTS: Of 756 (0.3%) inductions, 212 (28%) used prostaglandins (108 prostaglandin E1, 94 prostaglandin E2), and 553 (72%) used nonprostaglandin methods, including oxytocin (348, 63%), amniotomy (211, 38%), and/or mechanical dilation (9, 1%). There were no differences in the composite of adverse neonatal outcomes between the prostaglandin (10.4%) and the nonprostaglandin group (6.7%), adjusted odds ratio, 1.39 (0.64-3.03). The rate of cesarean delivery was higher in the inductions that received prostaglandins than those that did not (25.5% vs 14.8%, adjusted odds ratio, 1.80; 1.07-3.02). The rate of cesarean delivery for nonreassuring fetal heart tracings was higher for those that received prostaglandins than those that did not (16.0% vs 8.7%, adjusted odds ratio, 2.37; 1.28-4.41). When prostaglandin E1 and prostaglandin E2 were examined independently, there were similar increases in the composite of adverse neonatal outcomes and cesarean delivery rates for both prostaglandin E1 and prostaglandin E2 compared with nonprostaglandin controls. CONCLUSION: There were no differences in the composite of adverse neonatal outcomes when prostaglandins were used for induction in pregnancies with fetal growth restriction compared with other methods. However, there was a higher rate of cesarean delivery and cesarean delivery indicated for nonreassuring fetal heart tracings when prostaglandins (both prostaglandin E1 and prostaglandin E2) were used, compared with nonprostaglandin methods.

Prostaglandins for Postpartum Hemorrhage: Pharmacology, Application, and Current Opinion.

BACKGROUND: Postpartum hemorrhage (PPH) remains a common cause of maternal mortality worldwide. Medical intervention plays an important role in the prevention and treatment of PPH. Prostaglandins (PGs) are currently recommended as second-line uterotonics, which are applied in cases of persistent bleeding despite oxytocin treatment. SUMMARY: PG agents that are constantly used in clinical practice include carboprost, sulprostone, and misoprostol, representing the analogs of PGF2α, PGE2, and PGE1, respectively. Injectable PGs, when used to treat PPH, are effective in reducing blood loss but probably induce cardiovascular or respiratory side effects. Misoprostol is characterized by oral administration, low cost, stability in storage, broad availability, and minimal side effects. It remains a treatment option for uterine atony in low-resource settings, but its effectiveness as a uterotonic for independent application may be limited. Key Messages: The present review article discusses the physiological roles of various natural PGs, evaluates the existing evidence of PG analogs in the prevention and treatment of PPH, and finally provides a reference to assist obstetricians in selecting appropriate uterotonics.

Cortical hyperostosis, rare adverse effect of prostaglandin.

We describe here an infant girl with ductal dependent complex cyanotic heart disease, who required prostaglandin infusion for a total of five months prior to Blalock-Taussig shunt procedure. Her alkaline phosphatase activity was raised after seven weeks being on prostaglandin and only dropped to the normal range seven days after discontinuing prostaglandin infusion. During our review at five months old, her limbs were grossly swollen and radiographic examination showed dense periosteal reaction in the long bones. Based on the clinical findings and investigations, she was diagnosed to have cortical hyperostosis, which is an uncommon side effect of prostaglandin. She underwent right Blalock-Taussig Shunt procedure successfully with no major complications. Unfortunately, she succumbed to infection two months after surgery.

The Inhibitory Effect of Extra Virgin Olive Oil and Its Active Compound Oleocanthal on Prostaglandin-Induced Uterine Hypercontraction and Pain-Ex Vivo and In Vivo Study.

Primary dysmenorrhea is a common occurrence in adolescent women and is a type of chronic inflammation. Dysmenorrhea is due to an increase in oxidative stress, which increases cyclooxygenase-2 (COX-2) expression, increases the concentration of prostaglandin F2α (PGF2α), and increases the calcium concentration in uterine smooth muscle, causing excessive uterine contractions and pain. The polyphenolic compound oleocanthal (OC) in extra virgin olive oil (EVOO) has been shown to have an anti-inflammatory and antioxidant effect. This study aimed to investigate the inhibitory effect of extra virgin olive oil and its active ingredient oleocanthal (OC) on prostaglandin-induced uterine hyper-contraction, its antioxidant ability, and related mechanisms. We used force-displacement transducers to calculate uterine contraction in an ex vivo study. To analyze the analgesic effect, in an in vivo study, we used an acetic acid/oxytocin-induced mice writhing model and determined uterus contraction-related signaling protein expression. The active compound OC inhibited calcium/PGF2α-induced uterine hyper-contraction. In the acetic acid and oxytocin-induced mice writhing model, the intervention of the EVOO acetonitrile layer extraction inhibited pain by inhibiting oxidative stress and the phosphorylation of the protein kinase C (PKC)/extracellular signal-regulated kinases (ERK)/ myosin light chain (MLC) signaling pathway. These findings supported the idea that EVOO and its active ingredient, OC, can effectively decrease oxidative stress and PGF2α-induced uterine hyper-contraction, representing a further treatment for dysmenorrhea.

Can we induce labor by mechanical methods following preterm premature rupture of membranes?

OBJECTIVE: To evaluate the use of the intracervical balloon compared with locally applied prostaglandins for cervical ripening for induction in patients with preterm premature rupture of membranes. METHODS: Monocentric, retrospective (from 2002 to 2017) observational cohort study of singleton pregnancies complicated by preterm premature rupture of membranes and induced between 34 and 37 weeks. The primary outcome measure was balloon catheter efficiency evaluated by Cesarean section rate. Secondary outcomes were : interval from induction to delivery, labor duration, oxytocin use, intrauterine infection rate, maternal complications (i.e., postpartum hemorrhage and endometritis), and neonatal complications. RESULTS: 60 patients had cervical ripening with prostaglandins alone and 58 had balloon catheter. Demographic characteristics were similar between the groups, except for induction term and neonatal weight. There was not a significant difference in occurrence of Cesarean section rate (p = 0.14). Nor were there significant differences in time from induction to birth (p = 0.32) or in intrauterine infection rate (p = 0.95). Labor duration was shorter (p = 0.006) and total oxytocin dose lower (p = 0.005) in patients induced by prostaglandins alone. Concerning neonatal outcomes, there were more transfers to intensive care (p = 0.008) and more respiratory distress (p = 0.005) among newborns induced by prostaglandins. CONCLUSION: Compared with locally applied prostaglandins, balloon catheter induction is not associated with an increase of Cesarean section rate in patients with preterm premature rupture of membranes.

Induction of labor with an unfavorable cervix.

PURPOSE OF REVIEW: Recent evidence supports elective induction of labor after 39 weeks; however, labor induction in patients with an unfavorable cervix, a Bishop score less than 6, may take several days. In this review, we focus on the efficacy and safety of methods of labor induction for the unfavorable cervix. RECENT FINDINGS: Recent evidence on the use of mechanical cervical preparation with transcervical balloons suggests balloons are the most effective option for decreasing time to delivery in the nulliparous patient. Single and double balloons are equally effective, with a volume of more 30 ml being more effective. The addition of misoprostol or oxytocin concurrently with a balloon further expedites time to delivery. SUMMARY: Mechanical dilation should be considered when available and technically possible for labor induction in patients with an unfavorable cervix. Misoprostol is an effective adjunct to trans-cervical balloons, further decreasing time to delivery as compared with balloon alone. When misoprostol is contraindicated, oxytocin is a safe, effective, alternative adjunct to trans-cervical balloons. More research is needed to evaluate safe outpatient options, induction methods in the setting of prior cesarean with an unfavorable cervix, and to directly compare misoprostol with oxytocin as adjuncts to transcervical balloons.

What is the position of pulmonary arterial hypertension-specific drug therapy in patients with Eisenmenger syndrome: A systematic review and meta-analysis.

BACKGROUND: It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence. METHODS: PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test. RESULTS: Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death. CONCLUSIONS: This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.

[Cesarean after labor induction: Risk factors and prediction score]. / Césarienne après déclenchement du travail : facteurs de risque et score de prédiction.

OBJECTIVES: The objective of the study is to determine the risk factors for caesarean section at the time of labor induction, to establish a prediction algorithm, to evaluate its relevance and to compare the results with observation. METHODS: A retrospective study was carried out over a year at Nantes University Hospital with 941 cervical ripening and labor inductions (24.1%) terminated by 167 caesarean sections (17.8%). Within the cohort, a case-control study was conducted with 147 caesarean sections and 148 vaginal deliveries. A multivariate analysis was carried out with a logistic regression allowing the elaboration of an equation of prediction and an ROC curve and the confrontation between the prediction and the reality. RESULTS: In univariate analysis, six variables were significant: nulliparity, small size of the mother, history of scarried uterus, use of prostaglandins as a mode of induction, unfavorable Bishop score<6, variety of posterior release. In multivariate analysis, five variables were significant: nulliparity, maternal size, maternal BMI, scar uterus and Bishop score. The most predictive model corresponded to an area under the curve of 0.86 (0.82-0.90) with a correct prediction percentage ("well classified") of 67.6% for a caesarean section risk of 80%. CONCLUSION: The prediction criteria would make it possible to inform the woman and the couple about the potential risk of Caesarean section in urgency or to favor a planned Caesarean section or a low-lying attempt on more objective, repeatable and transposable arguments in a medical team.

Targeting therapeutics to bone by conjugation with bisphosphonates.

Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.

Prostanoids for critical limb ischaemia.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular disease in the general population. Although numerous treatments have been adopted for patients at different disease stages, no option other than amputation is available for patients presenting with critical limb ischaemia (CLI) unsuitable for rescue or reconstructive intervention. In this regard, prostanoids have been proposed as a therapeutic alternative, with the aim of increasing blood supply to the limb with occluded arteries through their vasodilatory, antithrombotic, and anti-inflammatory effects. This is an update of a review first published in 2010. OBJECTIVES: To determine the effectiveness and safety of prostanoids in patients with CLI unsuitable for rescue or reconstructive intervention. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (January 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). In addition, we searched trials registries (January 2017) and contacted pharmaceutical manufacturers, in our efforts to identify unpublished data and ongoing trials. SELECTION CRITERIA: Randomised controlled trials describing the efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments for patients presenting with CLI without chance of rescue or reconstructive intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. We resolved disagreements by consensus or by consultation with a third review author. MAIN RESULTS: For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids.We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life. AUTHORS' CONCLUSIONS: We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.

Incidence of Fever and Positive Bacterial Cultures in Neonates Receiving Prostaglandin.

Prostaglandin E (PGE1) is necessary to maintain ductus arteriosus patency in many newborns with congenital heart disease. Because PGE1 therapy commonly leads to fever, and given this population's fragile state, a complete sepsis workup is often performed in febrile, but otherwise asymptomatic, patients. This practice of liberal evaluation with bacterial cultures, empiric antibiotic treatment, and delays in essential surgical intervention may result in poor resource utilization and lead to increased iatrogenic morbidity. This study sought to determine the incidence of fever and culture-positive infection in patients receiving PGE1, and identify diagnostic variables that predict culture-positive infection. The study included a single-center retrospective review of all neonates receiving PGE1 between 2011 and 2014. Logistic regression and receiver operator characteristic analysis were used to identify significant predictors of positive bacterial cultures. Among 435 neonates, 175 (40%) had fevers (≥ 38.3 °C) while concurrently receiving PGE1, but only 9 (2%) had culture-positive infection and 1 (< 1%) had culture-positive bacteremia. Among 558 cultures collected, only 16 (3%) had bacterial growth. Multivariable analysis revealed age (p = 0.049, AUC 0.604), hospital length of stay (p = 0.002, AUC 0.764) and hypoxemia (p = 0.044, AUC 0.727) as the only significant predictors of positive cultures. Fever (p = 0.998, AUC 0.424) was not a significant predictor. In conclusion, given that fever occurs frequently in neonates receiving PGE1 and it is a very non-specific marker and not a predictor of positive cultures, the common practice of complete sepsis workup should be re-examined in febrile patients at low risk of bacterial illness.

A safety review of medications used for labour induction.

INTRODUCTION: Induction of labour is a commonly performed procedure around the world. There are various medications used for induction including those commonly used for cervical ripening (prostaglandins) and oxytocin. The ideal agent is one that decreases the time to achieving delivery without compromising maternal or neonatal safety. The 'optimal safe agent' remains undetermined. AREAS COVERED: This article reviews the safety of currently used induction agents. Prostaglandins and oxytocin have proven to be effective in labour induction, and their profiles will be reviewed in this article. We discuss the data that supports combining some of the agents. We also cover the safety of medications used for labour induction in setting of a scarred uterus. EXPERT OPINION: There is continuous debate about the ideal induction agent: one that balances safety with efficacy. We recommend the practice that there is not one perfect agent for all, and that the clinical scenario and previous obstetric history should be considered before choosing an agent. In the future, pharmacogenomics may show that genetics may affect the individual response and adverse reactions to the various agents.

[Update pulmonary arterial hypertension : Definitions, diagnosis, therapy]. / Update pulmonalarterielle Hypertonie : Definitionen, Diagnose, Therapie.

The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016.